Abstract:
Glioblastomas are the most frequent and aggressive form of primary malignant brain tumour. Despite the low incidence rate of glioblastomas, their mortality rate is high. Due to the highly-vascularised nature of glioblastomas, vascular targeting agents have been proposed as potential treatment strategies. Vascular disrupting agents target the established tumour vasculature and cause a rapid and selective shutdown of vasculature that leads to secondary tumour cell death and rapid haemorrhagic necrosis. But, potential use of VDAs in treatments of glioblastomas has not been examined broadly. We have investigated the potential benefits of DMXAA, one of the most clinically advanced VDAs, in the treatment of glioblastoma. Luciferase tagged GL261-LUC2 cells were inoculated subcutaneously or intracranially and the anti tumour effects of DMXAA were investigated in these models. DMXAA treatment increased the overall survival rate by twenty days in subcutaneous GL261-LUC2 tumours. Co-administration of DMXAA with lenalidomide potentiated the effects of DMXAA and the overall survival rate of eighty days was achieved. Histological assessment of DMXAA`s antitumour activity also revealed a significant haemorrhagic necrosis 24h after a single dose of DMXAA in subcutaneous GL261-LUC2 tumours. However, DMXAA failed to induce significant haemorrhagic necrosis in intracranially inoculated GL261-LUC2 cells. The pharmacokinetic profile of DMXAA was investigated in plasma and brain samples by LC/MS analytical method. The maximum DMXAA concentration in the brain was 90 times lower than that of plasma and the AUC was approximately 100 times lower in brain tissues which indicated the inability of DMXAA to cross BBB. Presence of tumour and co-administration of DMXAA with lenalidomide did not alter the pharmacokinetic profile of DMXAA in brain. We have concluded that vascular disrupting agents can be effectively employed in treatment of glioblastomas. DMXAA produced high anti-tumour effects on subcutaneous GL261-LUC2 tumours and co-administration of DMXAA with lenalidomide potentiated its anti-tumour effects. But, DMXAA is unable to cross the BBB and due to the low concentration of DMXAA in brain, its anti-tumour activities are minimal against intracranial GL261-LUC2 cells. Thus, it is critical to find an approach that can compensate the effect of BBB to successfully deliver vascular disrupting agents into the brain or to synthesize new drugs that can cross the BBB efficiently.